Intraepithelial Lymphocytes of the Intestine

Abstract

The intestinal epithelium, which segregates the highly stimulatory lumen from the underlying tissue, harbors one of the largest lymphocyte populations in the body, intestinal intraepithelial lymphocytes (IELs). IELs must balance tolerance, resistance, and tissue protection to maintain epithelial homeostasis and barrier integrity. This review discusses the ontogeny, environmental imprinting, T cell receptor (TCR) repertoire, and function of intestinal IELs. Despite distinct developmental pathways, IEL subsets share core traits including an epithelium-adapted profile, innate-like properties, cytotoxic potential, and limited TCR diversity. IELs also receive important developmental and functional cues through interactions with epithelial cells, microbiota, and dietary components. The restricted TCR diversity of IELs suggests that a limited set of intestinal antigens drives IEL responses, with potential functional consequences. Finally, IELs play a key role in promoting homeostatic immunity and epithelial barrier integrity but can become pathogenic upon dysregulation. Therefore, IELs represent intriguing but underexamined therapeutic targets for inflammatory diseases and cancer.

Keywords: cytotoxicity; dietary signals; intraepithelial lymphocytes; microbiota; tissue adaptation; tolerance.

Figure 1.. Intraepithelial lymphocyte subsets

(a) Overview of IEL subset characteristics. (b) Expression of key genes by IEL subsets showing either negative, low, or high expression (single colors), or the proportion of cells with negative, low, or high expression (gradients). AhR; aryl hydrocarbon receptor; BTNL; butyrophilin-like; gLN, gut-draining lymph node; IEL, intraepithelial lymphocyte; TCR, T cell receptor.

Figure 2.. Antigen recognition by intestinal intraepithelial lymphocytes.

This figure depicts how the different intestinal IEL subsets can recognize potential antigens. TCRγδ⁺ nIELs are not MHC-restricted but can bind to BTNLs expressed by IECs (74). Antigen recognition by most TCRαβ⁺ IEL subsets is restricted by classical MHC class I or class II or by non-classical MHC class Ib present on the surface of APCs. IECs also express classical and non-classical MHC molecules and possess the machinery for antigen processing and presentation and can act as APC. TCRαβ⁺ CD8αα⁺ nIELs can recognize antigens in complex with classical MHCIa or MHCII and non-classical MHC Ib (47, 49). TCRαβ⁺ CD8αα⁺ nIELs are believed to recognize self-antigens although precise antigens have not been identified. CD8αβ⁺ pIELs are MHC class I-restricted and can recognize pathogens such as viruses. Whether they can also recognize dietary and microbiota antigens is not known. CD4⁺ pIELs are MHCII-restricted and can recognize dietary and microbiota-derived antigens (16, 33). Whether they can recognize pathogens has not been formally established. APC, antigen-presenting cell; BTNL; butyrophilin-like; IEC, intestinal epithelial cell; MHC, Major histocompatibility complex; nIEL, natural intraepithelial lymphocyte; pIEL, peripherally induced intraepithelial lymphocyte; TCR, T cell receptor.

Figure 3.. Accumulation and distribution of intraepithelial lymphocytes along the intestine.

(a) nIELs differentiate from thymic precursors that directly seed the intestinal epithelium after thymic maturation. Upon arrival in the epithelium, they adapt to the tissue and acquire CD8αα expression. BTNLs, MHC-like molecules drive the development, tissue accumulation, and function of TCRγδ T lymphocytes (74). pIELs differentiate from conventional CD4⁺ or CD8⁺ T cells that were generated in the thymus and primed in the gLNs by RA-producing APCs, resulting in activation and acquisition of gut-homing capabilities. They differentiate into IELs at the intestinal epithelium in a microbiota and diet dependent-manner. In SPF mice, nIELs are more abundant in the duodenum whereas pIELs are enriched in microbe-rich ileum (61). Abundant commensal Bacteroidetes species such as Parabacteroides goldsteinii and Bacteroides vulgatus provide TCR ligands for CD4⁺ pIELs (16). All IELs express the aryl hydrocarbon receptor (AhR) and depend on signaling from AhR ligands derived from diet and the microbiota. nIELs require dietary AhR ligands for their tissue maintenance (151) whereas tryptophan metabolites produced by commensals such as Lactobacillus reuteri promote the accumulation of CD4⁺ CD8αα ⁺ pIELs (126). (b) nIEL accumulation in the intestine begins immediately after birth and occurs independent of microbial and dietary stimulation. pIELs are nearly absent before weaning around 21–28 days of age, and accumulate in the intestine epithelium of adult mice in a microbiota and dietdependent manner. AhR, aryl hydrocarbon receptor; APC, antigen-presenting cell; BTNL; butyrophilin-like; gLN, gut-draining lymph node; IEC, intestinal epithelial cell; nIEL, natural intraepithelial lymphocyte; pIEL, peripherally induced intraepithelial lymphocyte; RA, retinoic acid; SPF, specific pathogen-free; TCR, T cell receptor.